Goal 2: Reduce Human Disease

Mitigating risks due to the RBC storage lesion and vulnerable patients

What are the underlying dependencies (genomic, metabolic, disease) in individual donors that either accelerate or delay the changes to red blood cells during refrigerated storage? What methods of preparation might protect patients from the risks posed by the accelerated degradation of RBCs provided by "poor storers"? What characteristics of individual patients make them particularly vulnerable to transfusion of red ...more »

Submitted by (@andrew.dunham)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The changes in red blood cells during refrigerated storage have been well documented and associated with negative clinical sequelae in the peer reviewed literature. While the impact of this so-called storage lesion does not impact every patient during every transfusion it is reasonable to expect that when a unit of blood is transfused to a particularly vulnerable patient from a donor that has red blood cells pre-disposed to degradation, stored in a manner that has allowed significant change to occur, the risk of a negative clinical sequelae is increased. In this case it will be important to understand what underlies the likelihood of a donors blood to store poorly, the changes that occur during storage that could impact vulnerable patients and design approaches to mitigate the degradation that could result.

Feasibility and challenges of addressing this CQ or CC :

We believe mitigating the impact of the storage lesion is feasible by reducing and controlling the oxygen concentration in the RBC unit prior to refrigerated storage. We are continuing our development of a device to do this and to generate the data demonstrating the effect of deoxygenation and anaerobic storage.

Name of idea submitter and other team members who worked on this idea : Andrew Dunham

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Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to target epigenetic mechanisms as new treatment options for hematologic disorders.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Advances in the field of epigenetics and the understanding of various epigenetic mechanisms has provided a completely new ensemble of therapeutic targets for treating hematologic disorders – both non-malignant and malignant. These mechanisms have enormous implications for understanding the molecular underpinnings of the normal orderly development of hematologic disorders. Although one of the greatest challenges in effectively treating hematologic disorders is the diversity of molecular abnormalities that underlie a disease, there are a number of common threads emerging, including alterations in proteins that function through epigenetic mechanisms. Additional research focusing on epigenetic alterations and emerging targets is needed to identify the role of such proteins in the development of hematologic disorders in order to design potential targeted treatments to counter their effects. This research will further lay the groundwork for precision medicine, and will help to provide more insight on potentially critical determinants of responsiveness to therapeutic regimens.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Goal 2: Reduce Human Disease

Blood Pressure Recommendation

What should be the systolic blood pressure goal for pharmacological treatment, and should it vary by age or by cardiovascular disease (CVD) risk category?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Feasibility and challenges of addressing this CQ or CC :

Despite fifty years of clinical trial research and forty years of national guideline activity, important clinical questions remain under intense scientific debate. The importance of these questions are underline by the scientific consensus that hypertension is most important cardiovascular risk factor globally, in fact, more important than even tobacco use.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 1: Promote Human Health

Study wellness instead of diseases by longitudinal follow-up of frequent and long term blood donors

Blood donors (especially young donors) in general represent healthy populations. Longitudinal follow-up of frequent and long term blood donors can be useful to establish data and sample sources for the study of wellness, instead of disease (especially for blood diseases). Not only it can be used as healthy controls, it can also be used to predict the wellness factors such as genetic variation, life style, exercise patterns, ...more »

Submitted by (@yanyunw)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Once such study is established, it can be used as a wellness model/control for many diseases and conditions. The longer we have the study, more useful it will become. This can help us to change or optimize our health care model, from treating diseases to maintain wellness.

Feasibility and challenges of addressing this CQ or CC :

This can be quite feasible as there are many frequent and long term donors. They care about others’ health as well as their own health. They are also very willing to support research. Follow-up can start from early adulthood.

 

With funding support this can be achieved.

Name of idea submitter and other team members who worked on this idea : Yanyun Wu

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Goal 2: Reduce Human Disease

What new methods of platelet preparation, processing, and storage are needed for hemostasis in various clinical conditions?

The limitations of 5-day 22˚ C storage significantly impacts platelet availability. It is critical that we develop new methods of collection, processing, storage to extend the storage time of platelets, and evaluate the use of whole blood. The attributes of these products must be understood to optimally alignment product attributes, clinical efficacy and safety with hemostatic needs in a variety of clinical states. Specifically, ...more »

Submitted by (@bldbuddy)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Limitations of current storage methods challenge our ability to meet the increasing demands of cancer chemotherapy and complex surgeries as well as provide platelets to remote areas where trauma frequently occurs. Platelets are transfused to prevent or control bleeding without robust translational or clinical trial evidence of efficacy and safety. In patients with hypoproliferative thrombocytopenia receiving chronic platelet transfusion predominantly for prophylaxis, post-transfusion increments, survival time, and durable hemostatic efficacy are important; however, platelet transfusion alone does not prevent bleeding. The overall state of hemostasis, the endothelium and donor characteristics that affect platelet quality may be important considerations in selecting the best platelet product tailored to individual patients. Better laboratory and clinical measures of platelet function, efficacy and safety are essential for best use of these limited resources. These outcomes should span and link in-vitro testing, animal models, and clinical effects such as thrombotic events, immune, hemostatic, and endothelial effects. Extrinsic, recipient factors (e.g., immune deficiency, platelet or endothelial dysfunction) and intrinsic factors (e.g., donor specific or platelet preparation) should be considered. Systematic analysis of recipients and donors should be broad and include considerations of glycomics, metabolomics, proteomics, genomics, in vivo microscopy, and advanced imaging.

Feasibility and challenges of addressing this CQ or CC :

Radiolabeled platelet recovery and survival methods are well established and feasible to perform at several centers within the US. Currently 4-6 million units of platelets and whole blood are transfused per year. It is very feasible to conduct clinical trials that compare methods of platelet preparation, processing, and storage in children and adults who require platelets for either prophylaxis or active bleeding. Multiple research networks that focus on both pediatric and adult transfusion medicine are motivated to perform the pre-clinical and clinical trials required to establish improved efficacy and safety of platelet-containing blood products.

Name of idea submitter and other team members who worked on this idea : Terry Gernsheimer, University of Washington, for the 2015 NHLBI State of the Science in Transfusion Medicine

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Goal 2: Reduce Human Disease

Re-evaluating Hemoglobin Thresholds for Red Blood Cell Transfusion Decisions

Are there specific conditions where a liberal transfusion strategy results in lower 30-day mortality as compared to a restrictive transfusion strategy?

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

 Clinical trial data show that in multiple patient populations, a 7 to 8 g/dL hemoglobin threshold for red blood cell transfusion is safe. However, equipoise for transfusion thresholds persists in patients with ischemic heart disease and acute neurological conditions where a higher hemoglobin level may decrease ischemic injury to myocardial and cerebral tissues, respectively. Alternatively, liberal red blood cell transfusion may be associated with adverse outcomes such as pulmonary edema or increased rates of heart failure. In other populations, it is possible that even lower transfusion thresholds than 7 g/dL would be safely tolerated. On the other hand, if a 7 g/dL threshold is found to be superior to a lower threshold, this would establish a minimal appropriate threshold to initiate red blood cell transfusion.

Feasibility and challenges of addressing this CQ or CC :

Multicenter clinical trials that utilize markers of oxygen consumption are needed to answer these questions. A pilot study in patients with acute myocardial infarction demonstrated that recruitment was feasible for clinical scenarios in which equipoise exists. An international setting where the safety and availability of the blood supply remain significant issues may be best suited to answer the question of whether transfusion thresholds lower than 7 g/dL are safe.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Goal 2: Reduce Human Disease

Blood Donor and Component Factors that Influence Clinical Outcomes of Transfusion

Are donor factors (age/sex), whole blood processing methods and/or red cell storage solutions associated with in-hospital mortality and/or other measures of transfusion efficacy or harm in patients who have received red cell transfusions?

Submitted by (@anne.eder)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

There is growing evidence that donor factors (age, race-ethnicity, and/or sex), method of whole blood processing, and/or the additive solution used for red cell storage could affect the quality of the red cell product and contribute to patient adverse events. For example, red cell rigidity and oxygen saturation varies between premenopausal women and postmenopausal women and men, suggesting that donor age and/or sex may be important factors affecting red cell quality and patient outcomes. A retrospective Canadian study suggested that older blood was associated with in-hospital mortality until 2006; however, after that time the risk of in-hospital mortality increased when fresher blood was transfused. This change coincided with introduction of the buffy coat method suggesting that whole blood processing methods may affect patient outcomes.

Feasibility and challenges of addressing this CQ or CC :

The most efficient way to explore these issues is through the use of large dataset that can link donor demographics, product processing and recipient transfusion and outcome data. Recipient datasets are available and the feasibility of linking blood donor and blood product information has been demonstrated, making it possible to address the research question stated above.

Name of idea submitter and other team members who worked on this idea : Dana Devine PhD and Anne Eder MD PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Goal 3: Advance Translational Research

Genome Profiling

What structural changes need to be implemented in the health-care community in order to support the use of genomic information in clinical trials and drug development for hematologic diseases?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

In various blood disorders, including hematologic malignancies, there are both inherited and somatic genetic alterations that contribute to predisposition, transformation, disease progression, responsiveness to therapy, and treatment complications. The presence of such genetic alterations underscore the need for the identification of rare but traceable mutations as well as the integration of such genomic information into clinical trials. By implementing a few structural changes in the healthcare sector, a clinical trial infrastructure can be established that accounts for proper application of sequencing technology. Some examples include the creation of genome diagnostic networks that address accrual of sufficient patients, procurement of suitable tumor/non-tumor material for sequencing, as well as pharmacodynamic and correlative biology studies in hematologic diseases.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Goal 2: Reduce Human Disease

Inflammation: what is the role of the blood microbiome?

Blood is not continuously sterile. Data from dental studies, blood donors, and random blood cultures document that "normal" human blood often harbors microbes. Sepsis only occurs when immunological regulatory systems fail. Growing evidence link subclinical, potentially transient bacteremia to cardiovascular and other diseases. Could many of the diseases associated with inflammatory markers represent either continuous ...more »

Submitted by (@kevinfiscella)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

A central scientific question is whether the blood microbiome has immunologic significance or not. Does it represent a largely incidental, trivial finding or does it represent an important source for immunologic activity?

 

This change in scientific paradigm could have major implications for research including providing a unifying explanation for unexplained phenomena including potential mechanisms related to disparate conditions including CVD, HTN, preterm births, CNS disorders, auto-immune diseases, etc. For example, the inflammation associated with obesity may result from differences in not only the micriobiome of the GI tract but also blood. Transient bacteremia might also explain effects of psychologic stress, smoking, and diet via permeability effects via other microbiomes.

 

Historically, transient, subclinical bacteremia has been regarded as an incidental finding of little consequence outside of selected conditions e.g. bacterial endocarditis and severe immune suppression. The concept that subclinical, transient bacteremia (and potentially very low level viremia) have both beneficial (adaptive immunity) and harmful (inflammatory) significance creates new directions for research and ultimately new targets for intervention including regulators of permeability on various barriers between different microbiomes. e.g blood and GI tract, or blood and oral cavity etc.

Feasibility and challenges of addressing this CQ or CC :

One challenge is methodologic. Standard blood cultures miss low level and/or transient bacteremia. New approaches, e.g. 16 rDNA PCR etc offer promise but advances in methods are needed to capture potentially intermittent phenomena.

 

Another challenge is that the blood microbiome is likely polymicrobial and potentially dynamic with bursts of different microbes resulting from different sources e.g. oral cavity,skin, GI tract, UG tract, lung etc. Like other microbiomes, it is probably more of an ecological system embedded within other micorbiome systems. Methods need to account for for the potential large diversity in blood microbes with likely differing significance including potential competition and synergy between different microbes whether intra or extracellular.

 

A third challenge relates to the potential longitudinal and developmental implications. Potentially blood microbiome effects are relatively small, but cumulative and developmentally sensitive.This will require longitudinal studies in humans (and animal models) including studies done during pregnancy and other critical developmental periods.

 

A final challenge is modeling. This includes disentangling effects from established human microbiomes from the blood and establishing directions of effects between blood microbiomes and immune activity. Methods applicable to complex adaptive systems with non-linear, time dependent effects are likely required.

Name of idea submitter and other team members who worked on this idea : Kevin Fiscella, MD, MPH

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Goal 1: Promote Human Health

Iron Loss after Blood Donation and Its Effect on Donors’ Health

What is the effect of donation-induced iron deficiency on blood donor health?

Submitted by (@anne.eder)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Blood donation removes iron, and frequent blood donors commonly have low or absent iron stores. Donation frequency remains the strongest predictor of iron depletion among all donors, after controlling for body mass, race/ethnicity, and polymorphisms affecting iron metabolism. Less well documented is the effect of iron depletion on blood donor health and well-being. Iron deficiency may have a broad spectrum of physical and neurologic consequences, including impaired work capacity, altered cognitive function, pica and restless legs syndrome. The prevalence, duration, and severity of these conditions in blood donor populations are poorly elucidated. In contrast, modest iron deficits may be protective against cancer and cardiovascular disease. Some investigators have demonstrated the feasibility to connect donor information with clinical databases to study whether donation behavior and iron status have long-term consequences for donor health.

Feasibility and challenges of addressing this CQ or CC :

Studying the short-term clinical impact of donation-induced iron deficiency presents logistical and methodological challenges. Many outcomes of interest are not observable by blood center staff under routine procedures; further, such studies are subject to selection bias due to donor failure to return to donate following low hemoglobin deferral or adverse outcomes they associate with donation. However, given the size and demographic diversity of donor populations, even uncommon outcomes can be successfully studied under a multi-center approach. A prospective approach that doesn’t condition enrollment or completion of the study on return to donate, may avoid the methodological pitfalls. A wide array of clinical or neurological outcomes can feasibly be studied with sufficient blood centers and/or donor follow-up.

Name of idea submitter and other team members who worked on this idea : Dana Devine PhD and Anne Eder MD PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

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Goal 2: Reduce Human Disease

Anemia, oxygen delivery, and red blood cell transfusion

In neonatal, pediatric, and adult patients with critical illness, what is the best means to identify: (1) the degree to which anemia contributes to insufficient oxygen (O2) delivery and (2) the likelihood that O2 delivery will be improved by red blood cell (RBC) transfusion? These questions are most relevant to critically ill populations that exhibit unique physiology, including those with low cardiac output (cardiac ...more »

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

In the critically ill, RBC transfusion is indicated to improve O2 delivery. Although RBC transfusion increases hemoglobin concentration (Hb) and thereby blood O2 content, it does not necessarily follow that O2 delivery to tissues is likewise increased. Current approaches to transfusion decision making in critical care settings maintain an ‘adequate’ RBC mass well above a level that may limit tissue O2 delivery. With improved understanding of vascular signaling and gas transport by RBCs and of the array of defects comprising the RBC ‘storage lesion’, we appreciate that this strategy must be balanced by consideration that: (1) donor and recipient RBCs do not exhibit similar physiology and (2) RBC transfusion may cause harm (beyond transfusion reactions and transmission of infection) – and that this harm appears progressive with: transfusion volume, frequency and donor exposure. As such, ‘restrictive’ Hb thresholds for RBC transfusion are appreciated to be at least non-inferior to ‘liberal’ Hb thresholds for a broad array of conditions. A paradigm shift is emerging in approach to the critically ill, with re-consideration of the ‘Hb trigger’ strategy, itself. Ideally, the decision to transfuse should be based upon individual and context-specific consideration of the degree to which anemia contributes to tissue O2 delivery.

Feasibility and challenges of addressing this CQ or CC :

We need to identify specific physiologic endpoints linked to outcomes as well as determine the appropriate thresholds for these goals. We must improve current means to assess functionality of the circulating RBC mass and its specific relationship to tissue O2 delivery in both humans and animal models. Approaches to resolve this gap could be conducted in the following areas during the next 3-5 years (studies may be independent or ancillary to clinical transfusion trials). Examples include but are not limited to the following: (1) clinical and translational research studies examining physiologic tolerance of acute and chronic anemia in the critically ill populations; (2) basic and clinical research exploring accuracy, precision and reliability of novel approaches to quantify and monitor O2 consumption and delivery (global/regional). Investigations should also determine the relationship of these measures to clinically relevant patient outcomes, both global (mortality, ventilator dependence, length of stay, etc.) and organ-specific; and (3) studies evaluating the process of transfusion decision making in the setting of critical illness.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine.

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Goal 2: Reduce Human Disease

Prevent cytopenia in septic patients

Sepsis is the leading cause of death in critically ill patients in the USA, affecting particularly young children and the elderly. A hallmark of septic shock patients upon diagnosis is peripheral blood cytopenia. This persistent cytopenia commonly affects myeloid, lymphoid and erythroid lineages resulting in immunosuppression and is a well-established predictor of fatal outcome. Clinical trials targeting the production ...more »

Submitted by (@ben.croker)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The current standard-of-care for sepsis patients involves supportive therapy and the early administration of antibiotics, which has been essentially unchanged in 40 years. Therapies that prevent the loss of immune cells are likely to be beneficial to avoid immune suppression and prevent the development of life-threatening systemic infection.

Feasibility and challenges of addressing this CQ or CC :

One of the challenges of addressing this question are the large number of biochemical pathways that influence hematopoiesis. Most have not been studied in the context of infection in animal models or in clinical samples. But many animal models and reagents exist that would enable researchers to study this problem. The study of hematopoiesis during infection is feasible and a number of broad questions could be addressed:

a. Do hematopoietic cells and their precursors undergo cell death in response to intracellular pathogens leading to immune suppression?

b. Are hematopoietic cells and their precursors affected by extracellular pathogen-derived products or host-derived molecules resulting from severe injury? Does this lead to cell death and/or prevent the proliferation and differentiation of hematopoietic stem and progenitor cells?

c. How do genetic factors, chronic infection and comorbidities increase the activity of cell death pathways and/or impair the proliferation and differentiation of hematopoietic stem and progenitor cells?

Name of idea submitter and other team members who worked on this idea : Ben Croker

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